Abstract Mycobacterium tuberculosis (Mtb) is the most successful human pathogen, causing 1.8 million deaths in 2015. Accumulating evidence suggests that Mtb?s ability to survive, persist and cause disease is largely due to its ability to subvert the host immune and antimicrobial response to infection. Recent advances in immunometabolism have shown that a metabolic shift to glycolysis, aka the Warburg effect, is critical for the activation and differentiation of lymphocytes, dendritic cell maturation, and for M1 macrophage polarization, which is associated with microbial killing and effective control of infection. However, little is known about the metabolic state of immune cells during Mtb infection and its role in TB pathogenesis. Using transcriptomics and fluorescent IHC-assisted imaging, we found evidence for metabolic remodeling consistent with the Warburg effect during Mtb infection of macrophages ex vivo, as well as during Mtb infection in mouse, rabbit and human lungs. More intriguingly, we observed that infected macrophages at the center of granulomas showed decreased Warburg effect state compared to those at the periphery, suggesting that Mtb perturbs host cell metabolic switch to impair their pro-inflammatory and antimicrobial functions. Based on these and other data in the literature, we hypothesize that Mtb perturbs the Warburg effect to dampen APC polarization and function, compromising pro- inflammatory and antimicrobial functions of adaptive immunity and dampening macrophage activation, thus favoring the survival and persistence of the pathogen. To test our hypothesis, we propose three Specific Aims. First, we will determine the correlation between the Warburg effect state and macrophage polarization, activation and differentiation of T cells in granulomas in rabbit models of pulmonary active TB and latent infection, using fluorescent IHC- and single molecule RNA-FISH (smFISH)-based imaging. We will also perform metabolomic analysis of regions of granulomas at different stages of the differentiation and maturation. Second, we will perturb the Warburg effect by commercially validated therapeutic small molecule compounds and siRNA knockdown and analyze the effects of this perturbation on the effector functions of innate and adaptive immune cells ex vivo and in a mouse model of pulmonary TB in vivo. Third, we will use RNA-Seq and IHC- and smFISH-based imaging to dissect the metabolic/Warburg effect determinants responsible for the establishment of latency and for the reactivation. We will also characterize the effects of Warburg effect perturbation by small molecule therapeutic compounds on the host immune response and Mtb growth dynamics in a rabbit latency model. By elucidating the correlation between the Warburg effect and the functional potential of host innate and adaptive immunity in TB and its association with infection outcome, this study will establish an understanding of a novel aspect of Mtb pathogenicity. Outcomes of this study may lead to the development of host-directed therapies to target metabolism of immune cells to enhance their antimicrobial responses, facilitating efforts to control and eradicate this deadly disease.!